PMID- 35708885 OWN - NLM STAT- MEDLINE DCOM- 20220726 LR - 20220829 IS - 1865-8652 (Electronic) IS - 0741-238X (Print) IS - 0741-238X (Linking) VI - 39 IP - 8 DP - 2022 Aug TI - Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. PG - 3635-3653 LID - 10.1007/s12325-022-02170-w [doi] AB - INTRODUCTION: This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study. METHODS: Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (C(meanSS,nominal)) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade >/= 3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of C(meanSS,nominal). RESULTS: PK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade >/= 3 neutropenia, grade >/= 3 thrombocytopenia, grade >/= 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles. CONCLUSION: PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181. CI - (c) 2022. The Author(s). FAU - Samineni, Divya AU - Samineni D AUID- ORCID: 0000-0001-6300-2044 AD - Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA. samineni.divya@gene.com. FAU - Gibiansky, Leonid AU - Gibiansky L AD - QuantPharm LLC, North Potomac, MD, USA. FAU - Wang, Bei AU - Wang B AD - Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA. FAU - Vadhavkar, Shweta AU - Vadhavkar S AD - Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA. FAU - Rajwanshi, Richa AU - Rajwanshi R AD - VRAY Pharma Consulting, Cupertino, CA, USA. FAU - Tandon, Maneesh AU - Tandon M AD - Roche Products Ltd, Welwyn Garden City, UK. FAU - Sinha, Arijit AU - Sinha A AD - Roche Products Ltd, Welwyn Garden City, UK. FAU - Al-Sawaf, Othman AU - Al-Sawaf O AD - Faculty of Medicine, University of Cologne, Cologne, Germany. AD - Department I of Internal Medicine, German CLL Study Group, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, University Hospital Cologne, Cologne, Germany. FAU - Fischer, Kirsten AU - Fischer K AD - Faculty of Medicine, University of Cologne, Cologne, Germany. AD - Department I of Internal Medicine, German CLL Study Group, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, University Hospital Cologne, Cologne, Germany. FAU - Hallek, Michael AU - Hallek M AD - Faculty of Medicine, University of Cologne, Cologne, Germany. AD - Department I of Internal Medicine, German CLL Study Group, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, University Hospital Cologne, Cologne, Germany. FAU - Salem, Ahmed Hamed AU - Salem AH AD - AbbVie Inc., North Chicago, IL, USA. AD - Department of Clinical Pharmacy, Ain Shams University, Cairo, Egypt. FAU - Li, Chunze AU - Li C AD - Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA. FAU - Miles, Dale AU - Miles D AD - Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA. LA - eng SI - ClinicalTrials.gov/NCT02242942 SI - ClinicalTrials.gov/NCT02339181 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220616 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Bridged Bicyclo Compounds, Heterocyclic) RN - 0 (Sulfonamides) RN - N54AIC43PW (venetoclax) RN - O43472U9X8 (obinutuzumab) MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/pharmacokinetics MH - Bayes Theorem MH - Bridged Bicyclo Compounds, Heterocyclic MH - Humans MH - *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy MH - Sulfonamides PMC - PMC9309146 OTO - NOTNLM OT - Cancer OT - Drug safety OT - Effectiveness OT - Pharmacokinetics EDAT- 2022/06/17 06:00 MHDA- 2022/07/27 06:00 PMCR- 2022/06/16 CRDT- 2022/06/16 12:01 PHST- 2022/02/03 00:00 [received] PHST- 2022/04/21 00:00 [accepted] PHST- 2022/06/17 06:00 [pubmed] PHST- 2022/07/27 06:00 [medline] PHST- 2022/06/16 12:01 [entrez] PHST- 2022/06/16 00:00 [pmc-release] AID - 10.1007/s12325-022-02170-w [pii] AID - 2170 [pii] AID - 10.1007/s12325-022-02170-w [doi] PST - ppublish SO - Adv Ther. 2022 Aug;39(8):3635-3653. doi: 10.1007/s12325-022-02170-w. Epub 2022 Jun 16.